On a worldwide basis, leptospirosis is the most widespread zoonotic disease. Leptospirosis is also emerging as a significant infectious disease in urban slums, particularly in tropical regions. The infection is caused by spirochetes of the genus Leptospira, and can vary in severity from mild illness to fatal hemorrhagic disease with multiple organ failure. Pathogenicity can vary depending on the host species, host age and health status, and on the infecting strain. Virtually all species of mammals can serve as carriers, with the Leptospira persisting in the proximal tubules of the kidney and being shed in the urine. The persistence of leptospirosis in wildlife, companion animals, and livestock results in a continuous reservoir for human infection through exposure to animal tissue or body fluids containing Leptospira, or to urine-contaminated water sources. The bacteria enter through mucous membranes or skin abrasions, then disseminate to multiple tissues and can establish persistent infection in particular sites, such as the proximal tubules of the kidney. Adhesion to host cell surfaces and extracellular matrix (ECM) is critical to the pathogenesis of disease for many pathogens. This is likely to be true of Leptospira, as well, yet little is known about the adhesion mechanisms that Leptospira use to establish infection in their hosts. We have found that leptospires adhere more efficiently to mammalian cells than to the extracellular matrix (ECM), although most previous studies on adhesion mechanisms of Leptospira species have focused on interactions with the ECM. We have generated preliminary data that suggest that L. interrogans binds to particular glycosaminoglycans and integrins. Our long-term hypothesis is that adhesion to host cell surfaces will be an important determinant of the outcome of leptospiral infection, and will be critical for establishing a persistent infection in immunocompetent hosts. Our immediate goals for this proposal are to systematically identify and characterize the mammalian cell-surface glycosaminoglycans and integrins to which pathogenic Leptospira bind. Our long-term goal is to better understand the nature and consequences of Leptospira interactions with mammalian tissue components, which may eventually be useful in future development of novel vaccines or, potentially, therapeutic approaches. PUBLIC HEALTH RELEVANCE: Leptospirosis is a potentially fatal infectious disease with global distribution. The higher prevalence of leptospirosis in the developing world suggests that preventive measures, such as vaccines that are effective against diverse Leptospira strains, would have a significant impact on human and animal health. As a step toward development of improved vaccines, our long-term goal is to identify leptospiral and mammalian molecules required for these bacteria to cause infection and disease, and for the purposes of this proposal we will focus on identifying the mammalian cell surface receptors for L. interrogans.